title: Inferring selection intensity and allele age from multilocus haplotype structure.
abstract: It is a challenging task to infer selection intensity and allele age from population genetic data. Here we present a method that can efficiently estimate selection intensity and allele age from the multilocus haplotype structure in the vicinity of a segregating mutant under positive selection. We use a structured-coalescent approach to model the effect of directional selection on the gene genealogies of neutral markers linked to the selected mutant. The frequency trajectory of the selected allele follows the Wright-Fisher model. Given the position of the selected mutant, we propose a simplified multilocus haplotype model that can efficiently model the dynamics of the ancestral haplotypes under the joint influence of selection and recombination. This model approximates the ancestral genealogies of the sample, which reduces the number of states from an exponential function of the number of single-nucleotide polymorphism loci to a quadratic function. That allows parameter inference from data covering DNA regions as large as several hundred kilo-bases. Importance sampling algorithms are adopted to evaluate the probability of a sample by exploring the space of both allele frequency trajectories of the selected mutation and gene genealogies of the linked sites. We demonstrate by simulation that the method can accurately estimate selection intensity for moderate and strong positive selection. We apply the method to a data set of the G6PD gene in an African population and obtain an estimate of 0.0456 (95% confidence interval 0.0144-0.0769) for the selection intensity. The proposed method is novel in jointly modeling the multilocus haplotype pattern caused by recombination and mutation, allowing the analysis of haplotype data in recombining regions. Moreover, the method is applicable to data from populations under exponential growth and a variety of other demographic histories.
authors.affiliation: Department of Integrative Biology, University of California, Berkeley, California 94720, USA. hchen007@gmail.com
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.forename: Montgomery
authors.initials: M
authors.lastname: Slatkin
mesh_terms: D000465:Algorithms; D000483:Alleles; D044383:Black People / Q000235:genetics; D056426:Genetic Loci; D005828:Genetics, Population; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008957:Models, Genetic; D012641:Selection, Genetic
chemical_list: D005954:Glucosephosphate Dehydrogenase
keywords: allele age; haplotype structure; importance sampling; selection coefficient; structured coalescent; time-varying population size